Recently we have been successful in the detection and validation of a novel optical signal associated with peripheral nerve activation in the human. The evidence collected to date supports the hypothesis that the origin of this optical signal is derived from a novel and surprisingly fast-acting neurovascular coupling process associated with the peripheral nerve. The existence of neurovascular coupling in the peripheral nerve is potentially important clinically because it represents a homeostatic process whose disruption may underlie the pathobiology of nerve disease in aging, diabetes and toxic injury. In this proposal we will test the central hypothesis that the near-infrared spectrophotometric (NIRS) signal measured in the peripheral nerve is a result of an intrinsic and normal physiological neurovascular coupling mechanism. First we will adapt our current NIRS instrumentation, probe design, test paradigms and data analysis algorithms to a rat model and using an in vivo sciatic nerve preparation carry out experiments to determine the nature of the anatomical compartment and the stimulus-response relationship coupling to metabolic demand in NIRS. Second we will test the hemodynamic origin of the signal by examining the full spectral fingerprint of the signal and tagging blood with an optical imaging agent. Finally we will establish which component of the NCS-NIRS signal originates from adrenergic, cholinergic or from local signaling pathways by infusing specific agonists and antagonists of 1, 2 , muscarinic, nicotinic receptors and by activating and blocking nitric oxide and adenosine in local pathways. PUBLIC HEALTH RELEVANCE: This research is a translational in bringing new technology and knowledge to the care of patients with nervous system disease especially involving the disease and aging of the peripheral nervous system. This research may help physicians diagnose and treat the nerve damage from diabetes, chemotherapy and environmental toxins that cause significant pain and loss of function and are a burden on individuals and society. This new signal may be a useful target for early clinical diagnosis and potentially intervention of diseases that affect the peripheral nervous system disease.